Project Summary Atopic dermatitis/AD (atopic eczema) is a chronic, inflammatory disease resulting in itchy, inflamed, swollen skin that is easily susceptible to infection. It is estimated by the National Eczema association that there are currently 31.6 million people affected, and at least 17.8 million of them have moderate to severe disease. The current standard of care largely comprises of a multipronged approach involving skin care, elimination of allergic triggers and immune-suppressive strategies including the use of steroids, antihistamines, or topical immunommodulators (TIMs). While these therapies can help partly manage the disease, undesirable side effects are seen upon chronic usage. Thus, given the significant public health burden imposed on the society and the lack of effective treatments, there is an unmet need for novel targeted therapeutics that can help manage symptoms and improve the quality of life for AD patients Fannin Partners, LLC is an early-stage life sciences development group focused on commercializing innovation developed in the Texas Medical Center institutions. Led by an experienced team of managers with diverse business backgrounds, commercialization experience, and strong entrepreneurial knowhow, Fannin Partners works with promising life science innovators to help develop and commercialize promising therapeutic technologies for clinical adoption. The basic research conducted by Drs. John McMurray and David Corry directly led to this innovation. Our lead molecule, PM-43I, is a small-molecule, cell-permeable, and phosphatase-stable phosphopeptide mimetic that targets the SH2 domain of STAT6 and prevents recruitment to IL-4R? and the subsequent transcriptional activity leading to the atopic dermatitis phenotype. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization for the atopic dermatitis market by conducting in vitro and in vivo proof of concept study. The project is organized into two measureable Specific Aims: 1. Characterization of STAT6 phosphorylation and skin barrier gene expression in human keratinocytes in the presence of PM-43I. Keratinocytes play a critical role in AD pathogenesis. They show upregulated STAT6 phosphorylation upon IL- 4 and IL-13 stimulation. Phosphorylated STAT6 then down-regulates the level of loricrin and ivolucrin, two proteins important for skin barrier formation and integrity. Our previous studies in asthma have demonstrated that PM-43I is able to reduce STAT6 phosphorylation in lung epithelial cells (data not shown), here we are going to test if PM-43I also reduces STAT6 phosphorylation in keratinocytes, and subsequent down-regulation of LOR and IVL expression. 2. To study the efficacy of PM-43I in atopic dermatitis management. Specific Aim 2A: To determine PM-43I formulation for animal study. (2 months) This aim is going to determine the best-performing topical formulation for PM-43I in treating atopic dermatitis for the following efficacy study in mouse models. Drug solubility, stability, and in vitro skin permeation will be studied. Specific Aim 2B: To study the efficacy of PM43I in atopic dermatitis animal models (7 months) With the formulation obtained from Aim 2A, we will employ atopic dermatitis mouse model to study the efficacy of PM-43I in this aim. AD clinical score will be used to evaluate the symptoms of mice with or without PM-43I treatment. In addition, histology, serum cytokines and IgE level, and STAT6 phosphorylation and skin barrier gene expression in keratinocytes will be examined. These studies will help to prove the function of PM-43I in atopic dermatitis on both the symptomatic and molecular level.